Regulation of Skeletal Muscle LKB1

骨骼肌 LKB1 的调节

• 批准号: 7434563
• 负责人: WILLIAM WINDER
• 金额: $ 31.4万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434563
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Alcar; Calcium; Complex; Contracts; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Enzymes; Exercise; GLUT4 gene; Genetic Transcription; Heat-Shock Proteins 90; Hepatocyte; Hexokinase 2; Knockout Mice; Laboratories; Mammalian Cell; Mitochondria; Mus; Muscle; Muscle Contraction; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmacologic Substance; Phosphorylation; Population; Prevention; Proteins; Purpose; Recombinant Proteins; Regulation; Reporting; Rest; Role; STK11 gene; Signal Transduction; Skeletal Muscle; System; Tumor Suppressor Proteins; design; fatty acid oxidation; glucose uptake; hexokinase; insulin sensitivity; research study; response; sedentary

DESCRIPTION (provided by applicant): LKB1 was reported in September 2003 to be a component of the AMP-activated protein kinase (AMPKK) activity in extracts of liver and of cells in culture. AMPKK phosphorylates and activates AMPK which then phosphorylates proteins involved in stimulation of fatty acid oxidation, stimulation of glucose uptake, increasing insulin sensitivity and in controlling content of hexokinase, GLUT4, and mitochondria! oxidative enzymes in skeletal muscle. AMPKK and AMPK are activated in muscle in response to muscle contraction. Because of the well-demonstrated effects of AMPK activation on glucose uptake, fatty acid oxidation, GLUT4 expression, and insulin sensitivity, this signaling system has been targeted for development of Pharmaceuticals for prevention and treatment of type 2 diabetes. We have recently developed a muscle specific LKB1 knockout mouse in our laboratory that will enable elucidation of roles and mechanisms of activation and actions of the tumor suppressor protein, LKB1, in skeletal muscle. More specifically, these experiments will verify that LKB1 is a component of the AMPKK complex in skeletal muscle and provide new information regarding its regulation. The specific proteins associating with LKB1 in resting and contracting muscle to produce AMPKK activity will be determined. Using recombinant proteins expressed in mammalian cells we will determine which components of the LKB1 complex (postulated to be LKB1, STRAD, MO25 and HSP90) are essential for AMPKK activity. The mechanisms of activation of LKB1 in muscle will be investigated. Finally, the mechanisms of enhancement of GLUT4 transcription by LKB1 and AMPK in skeletal muscle will be studied. This information will be crucial for design of Pharmaceuticals targeting this pathway for treatment of type 2 diabetes. The proposed studies will provide additional rationale for convincing a predominantly sedentary population of the importance of regular exercise in combating inactivity-related diseases.

描述（由申请人提供）：2003年9月报道LKB1是肝脏和培养细胞提取物中AMP激活蛋白激酶（AMPKK）活性的组成部分。 AMPKK 磷酸化并激活 AMPK，然后磷酸化参与刺激脂肪酸氧化、刺激葡萄糖摄取、增加胰岛素敏感性以及控制己糖激酶、GLUT4 和线粒体含量的蛋白质！骨骼肌中的氧化酶。 AMPKK 和 AMPK 在肌肉中因肌肉收缩而被激活。由于 AMPK 激活对葡萄糖摄取、脂肪酸氧化、GLUT4 表达和胰岛素敏感性具有良好的影响，因此该信号系统已成为预防和治疗 2 型糖尿病药物开发的目标。我们最近在实验室开发了一种肌肉特异性 LKB1 敲除小鼠，这将能够阐明肿瘤抑制蛋白 LKB1 在骨骼肌中的作用和激活机制以及作用。更具体地说，这些实验将验证 LKB1 是骨骼肌中 AMPKK 复合物的组成部分，并提供有关其调节的新信息。将确定在休息和收缩肌肉中与 LKB1 相关以产生 AMPKK 活性的特定蛋白质。使用在哺乳动物细胞中表达的重组蛋白，我们将确定 LKB1 复合物的哪些成分（假设为 LKB1、STRAD、MO25 和 HSP90）对于 AMPKK 活性至关重要。将研究肌肉中 LKB1 的激活机制。最后，将研究骨骼肌中LKB1和AMPK增强GLUT4转录的机制。这些信息对于针对该途径治疗 2 型糖尿病的药物设计至关重要。拟议的研究将为让以久坐为主的人群相信定期锻炼对于对抗与缺乏活动相关的疾病的重要性提供更多依据。